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Common Variable Immunodeficiency

Common Variable Immunodeficiency (CVID) is an inborn immune disorder characterised by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM, and IgA.

Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract. CVID affects males and females equally and can be diagnosed at any age, although it is more commonly recognised in adulthood.

Signs and Symptoms

The symptoms of CVID vary greatly among individuals. The main features include hypogammaglobulinaemia and recurrent infections. Hypogammaglobulinaemia is marked by a significant decrease in the levels of IgG antibodies, often accompanied by decreased IgA and sometimes IgM antibodies. Common infections include pneumonia, ear infections, sinusitis, chronic coughing, and gastrointestinal infections. The pathogens most frequently causing infections in CVID patients are Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus.

Autoimmune disorders are frequently associated with CVID, with reported prevalence ranging from 14% to 54%. Common autoimmune manifestations include autoimmune cytopenia, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anaemia (AIHA), and neutropenia. CVID patients also have a higher risk of malignancies, particularly Non-Hodgkin lymphoma (NHL) and gastric carcinoma. Gastrointestinal complications and lymphocytic infiltration of tissues are also common, leading to conditions such as chronic gastritis and granulomatous-lymphocytic interstitial lung disease.

Diagnosis

Diagnosis of CVID is primarily by exclusion. It involves confirming a significant decrease in serum IgG levels and a marked decrease in at least one of the isotypes IgM or IgA, with the individual being four years of age or older. Other causes of hypogammaglobulinaemia must be excluded. Differential diagnoses vary by age group and include conditions such as leaky SCID, transient hypogammaglobulinaemia of infancy, X-linked agammaglobulinaemia (XLA), and thymoma.

Treatment

Treatment options are limited and usually involve lifelong immunoglobulin replacement therapy. This therapy replenishes the Ig subtypes that the patient lacks and helps reduce bacterial infections and boost immune function. Infusions can be administered intravenously (IVIg), subcutaneously (SCIg), or intramuscularly (IMIg). Adverse side effects from immunoglobulin infusions can include swelling at the insertion site, chills, headache, nausea, fatigue, muscle aches, fever, hives, thrombotic events, aseptic meningitis, and anaphylactic shock.

In addition to immunoglobulin replacement therapy, treatment may also involve immune suppressants to control autoimmune symptoms of the disease and high-dose steroids like corticosteroids. Antibiotics may be used to fight chronic lung disease resulting from CVID. The prognosis varies greatly depending on the level of lung and other organ damage prior to diagnosis and treatment.

Pathogenesis

The exact cause of CVID is not fully known. Genetic mutations can be identified in about 10% of cases, and familial inheritance accounts for 10–25% of cases. Rather than arising from a single genetic mutation, CVID seems to result from a variety of mutations that contribute to a failure in antibody production. Mutations in genes encoding ICOS, TACI, CD19, CD20, CD21, CD80, and BAFFR have been identified as causative of CVID. Several recent studies have described a potential role of epigenetic factors in the pathogenesis of CVID.

Epidemiology

CVID has an estimated prevalence of about 1 in 50,000 in Caucasians, with males and females equally affected. Among children, boys predominate. A study of individuals in Europe with primary immunodeficiencies found that 30% had CVID. The disease seems to be less prevalent among Asians and African Americans. CVID shortens lifespan, with one study suggesting a median age of death for men and women to be 42 and 44 years old, respectively, although most patients in the study were still alive. Those with accompanying disorders had the worst prognosis, while those with only CVID-caused frequent infections had the longest survival rates.


Self-assessment MCQs (single best answer)

Which immunoglobulins are typically low in patients with Common Variable Immunodeficiency (CVID)?



What is the estimated prevalence of CVID in Caucasians?



Which of the following is NOT typically associated with CVID?



Which autoimmune conditions are commonly associated with CVID?



What is the primary method of treatment for CVID?



Which of the following genes have been identified as causative of CVID?



Which age group is most commonly diagnosed with CVID?



Which of the following pathogens is NOT commonly associated with infections in CVID patients?



What percentage of CVID cases have identifiable genetic mutations?



Which of the following is a common gastrointestinal complication in CVID patients?



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